Functional role of the thalamus in coordinating dorsolateral striatum encoding of habit learning

The National Institute on Drug Abuse awarded The Medical University of South Carolina $100,228 on January 14, 2027, under the Drug Use and Addiction Research Programs (CFDA 93.279) to support research into the functional role of the thalamus in coordinating dorsolateral striatum encoding of habit learning.

The research addresses how the paraventricular thalamus regulates the neural mechanisms underlying the transition from flexible, goal-directed behavior to automatic habitual behavior—a disruption in this balance that constitutes core pathology in substance use disorder and other neuropsychiatric conditions. The project uses optogenetic activation and circuit-level analysis to characterize how thalamic inputs modulate population-level computations in the dorsolateral striatum and inhibitory interneurons, with preliminary findings showing that paraventricular thalamus terminal activation in the dorsolateral striatum attenuates habitual responding.

Work is performed in Charleston, South Carolina. The period of performance runs through July 31, 2029. This is a Project Grant, a standard assistance type under the Drug Use and Addiction Research Programs, which funds basic, clinical, translational, and implementation research to develop prevention, diagnosis, and treatment approaches for drug use, misuse, addiction, and related outcomes.

Abstract

Behavioral control is dynamically regulated by the interplay between flexible, goal-directed actions and efficient, automatic habits. Goal-directed behavior, driven by knowledge of the action-outcome (a-o) relationship, allows for behavioral flexibility, while habits are automatic responses that persist despite changes in outcome value. The disruption of this balance, where the habit system dominates flexible control, constitutes the core pathology underlying persistent, compulsive behaviors seen across many neuropsychiatric disorders, including substance use disorder (SUD). Defining the neural mechanisms that support the emergence of habitual behavior is essential for identifying how and when this process becomes maladaptive. Although extensive preclinical research has established the dorsolateral striatum (DLS) as required for the expression of habitual behavior, the upstream, circuit-level mechanisms that modulate this behavioral transition remain poorly understood. Specifically, how upstream inputs alter population-level computations-such as ensemble structure and network dynamics-to drive the shift from goal-directed to habitual behavior remains a critical knowledge GAP. One promising candidate for regulating this process is the paraventricular thalamus (PVT), a region known for its role in top-down control of motivated behavior. Previous findings from our lab have shown that PVT projections can inhibit goal-directed behavior by engaging inhibitory interneurons in the nucleus accumbens (NAC), which in turn regulate the activity of striatal output neurons. My preliminary data extends this work to the DLS, demonstrating that the PVT also robustly innervates inhibitory interneurons in this region. Functionally, optogenetic activation of PVT terminals in the DLS resulted in a significant attenuation of habitual responding, suggesting that PVT- DLS signaling influences the emergence of habitual behavior by modulating DLS circuit activity. My overarching hypothesis is that PVT projections to the DLS regulate the transition between goal-directed and habitual behavior through feedforward inhibition of DLS output neurons. To test this hypothesis, in aim 1 i will use optogenetics to determine the functional necessity of PVT-DLS output circuitry for goal-directed and habit-like behaviors. Next, in aim 2 i will use in vivo calcium imaging in a validated head-fixed paradigm to track DLS neuronal activity as mice transition from goal-directed to habitual behavior, determining how PVT input influences ensemble recruitment and population-level firing patterns. Ultimately, this research aims to provide crucial insight into how thalamostriatal signaling regulates the balance between goal-directed and habitual control. By defining the circuit mechanisms that drive behavioral inflexibility, this work will offer new avenues for intervention in SUD and other neuropsychiatric disorders characterized by compulsive, habitual behavior (e.g., OCD, tourette's syndrome).